Achieving Long Timescale Sampling in Biomolecular Simulations

在生物分子模拟中实现长时间尺度采样

• 批准号: 0919983
• 负责人: Wei Yang
• 金额: $ 44.36万
• 依托单位: Florida State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0919983&HistoricalAwards=false
• 关键词: Achieving; Long; Timescale; Sampling; Biomolecular

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).The objective of this research is to develop and apply efficient simulation methods to quantitatively describe complex biomolecular phenomena that usually occur in longer timescale than what conventional methods can achieve. Molecular recognition such as protein-ligand recognition and large conformational transition are two key elements in biomolecular machines. Due to timescale limitation, quantitative understanding of these events via computer simulation has been very challenging. In this project, efficient generalized ensemble simulation methods will be developed and employed to enhance the sampling power of biomolecular simulations. The promise of this project is particularly ensured by a recent methodological development in the PI's lab: the orthogonal space random walk (OSRW) algorithm, which can uniquely realize collective environmental relaxation in a robust and efficient manner. Specifically, three aims will be targeted: (1) understanding protein-protein interactions and protein electrostatics via OSRW based free energy simulations; (2) developing a hybrid quantum mechanical/molecular mechanical (QM/MM) based OSRW sampling scheme to more accurately describe protein-ligand interactions; (3) developing OSRW based conformational sampling methods to predict protein functional dynamics. In recent years, the PI has made tremendous efforts in organizing workshops and meetings to connect computational biophysics and experimental biophysics and to bridge method developments and biological applications. Some of these workshops, for instance, Telluride workshop on sampling enhancement, have become standing ones. In particular, the PI has been putting enormous emphasis in building multi-layered environments for young scientists so that they can receive suitable education to carry out multi-disciplinary research. In order for the advanced methods that are recently developed in the groups of PI and others to be quickly absorbed by the scientific community, the PI edited a special issue on free energy simulation in Journal of Computational Chemistry in early 2009 and is co-writing a book that is focused on modern simulation methods and their hand-on application. In addition, the developed methods through this project will be released in the program CHARMM, which can be widely employed by general scientific community.

该奖项是根据2009年美国复苏和再投资法案(公法111-5)资助的。这项研究的目标是开发和应用有效的模拟方法来定量描述复杂的生物分子现象，这些现象通常发生在比传统方法更长的时间尺度上。分子识别，如蛋白质-配体识别和大构象转变，是生物分子机器的两个关键要素。由于时间尺度的限制，通过计算机模拟来定量理解这些事件一直是非常具有挑战性的。在本项目中，将开发和使用高效的广义系综模拟方法来提高生物分子模拟的采样能力。这个项目的前景得到了PI实验室最近一项方法论的发展：正交空间随机行走(OSRW)算法的特别保证，该算法可以唯一地以稳健和高效的方式实现集体环境放松。具体地说，目标有三：(1)通过基于OSRW的自由能模拟来理解蛋白质-蛋白质相互作用和蛋白质静电学；(2)发展基于混合量子力学/分子力学(QM/MM)的OSRW抽样方案以更准确地描述蛋白质-配体相互作用；(3)发展基于OSRW的构象抽样方法来预测蛋白质功能动力学。近年来，国际生物物理学学会在组织研讨会和会议方面做出了巨大努力，将计算生物物理学和实验生物物理学联系起来，并将方法开发和生物学应用联系起来。其中一些讲习班，例如关于加强抽样的特利德讲习班，已经成为常设讲习班。特别是，PI一直非常重视为青年科学家建立多层次的环境，使他们能够接受适当的教育，开展多学科的研究。为了让PI和其他小组最近开发的先进方法迅速被科学界吸收，PI于2009年初在《计算化学杂志》上编辑了一期关于自由能模拟的特刊，并正在与人合著一本书，重点是现代模拟方法及其实际应用。此外，通过该项目开发的方法将在CHARMM程序中发布，该程序可广泛应用于普通科学界。